It has now been found that a pharmaceutical composition comprising a cannabinoid, such as cannabidiol, or a cannabinoid prodrug, such as a cannabidiol prodrug, can be transdermally administered to a mammal in conjunction with a microneedle array to treat a medical condition responsive to cannabinoids, such as alcohol use disorders, pain, inflammation and pancreatic diseases, such as pancreatic cancer and pancreatitis, via transdermal or topical drug delivery systems. It has further been found that microneedle transdermal or topical drug delivery systems comprising a pharmaceutical composition, comprising a cannabinoid or cannabinoid prodrug and a penetration enhancer (i.e., co-solvent), and a microneedle array can be used to treat a medical condition responsive to cannabinoids, such as alcohol use disorders, pain, inflammation and pancreatic diseases, such as pancreatic cancer and pancreatitis. It has further been found that microneedle transdermal or topical drug delivery systems comprising a pharmaceutical composition, comprising a cannabinoid or cannabinoid prodrug, a microneedle array and a COX inhibitor, such that the duration in which the microneedle created pore will remain open is increased, can be administered to a mammal. Suitable COX inhibitors include diclofenac and ibuprofen.
The pharmaceutical compositions described herein are suitable for use with a COX inhibitor-containing gel or hydrogel which has been optionally incorporated into a patch. In one embodiment, the COX inhibitor-containing gel or hydrogel which has been optionally incorporated into a patch is distinct from the pharmaceutical composition containing a cannabinoid or a cannabinoid prodrug and is applied to the skin surface either before, during or after the skin has been treated with a microneedle array. In another embodiment, the pharmaceutical compositions comprising the cannabinoid or cannabinoid prodrug further comprises a COX-inhibitor and is administered as a gel or hydrogel which has been optionally incorporated into a patch that is applied to the skin surface either before, during or after the skin had been treated with a microneedle array.
Cannabinoids and Cannabidiol
Cannabinoids, including cannabidiol (“CBD”), have recently been found useful in treating pancreatic illnesses. For example, it has been found that cannabidiol is useful in the treatment of acute and chronic pancreatitis. Pancreatitis is widely known as a very painful disease and can ultimately lead to pancreatic cancer. It has been found that cannabidiol has anti-inflammatory activity that results in a decrease of pain in pancreatitis cases. Pancreatic cancer is the fourth most common fatal cancer in the United States and fifth most prevalent worldwide. Cannabinoids, such as tetrahydrocannabinol and the synthetic cannabinoid WIN 55,212-2, have been found to induce apoptosis of pancreatic tumor cells in vitro and in vivo. Cannabidiol has the same potential to cause the same cascade that results in tumor cell death and diminish proliferation to lateral tumor formation.
In addition, the clinical usefulness of cannabinoids, including cannabidiol, to provide analgesia and neuroprotection, reduce inflammation, help alleviate nausea and emesis, as well as treat epilepsy, anxiety disorders and glaucoma, has been well-recognized. In addition, it is also well-known that cannabidiol lacks the psychoactive effects seen in many of the other cannabinoids, including Δ9-tetrahydrocannabinol, which is currently available in an oral dosage form, sold under the trade name Marinol®.
Pain is the most frequently reported symptom and it is a common clinical problem confronting all clinicians. Millions of people in the United States suffer from severe pain that, according to numerous recent reports, is chronically under-treated or inappropriately managed. Similarly, millions of people also suffer from severe nausea and/or frequent emesis. Moreover, all too frequently, many patients suffering from chronic, under-treated or irretraceable pain also suffer from lack of appetite, nausea and/or frequent emesis. These patients present a greater clinical challenge as they are unable to receive effective doses of oral pain medications, thereby leaving their pain unalleviated. Cannabinoids, including cannabidiol, are effective in alleviating pain. Moreover, cannabinoids, including cannabidiol, can reduce a patient's nausea and vomiting, independent of any pain relief achieved. Thus, cannabinoids are particularly useful in patients experiencing nausea and vomiting secondary to un- or under-treated pain.
A notable percentage of the United States population satisfy the diagnostic criteria for alcohol use disorders (“AUDs”). The consumption of excessive amounts of alcohol results in a complex array of pharmacological effects that directly impact the ability to treat the condition. These effects directly impact the brain and include progressive neurodegeneration, impaired executive function and dependence leading to withdrawal-induced negative effects. It is known that cannabinoids, including cannabidiol, have neuroprotective, anxiolytic and anti-convulsant effects, which may be effective in preventing additional brain damage in persons with AUDs, while simultaneously decreasing the frequency of relapses.
Chronic abusers of cannabis can develop dependence and experience withdrawal symptoms when they attempt to discontinue use of the drug. Collectively, cannabis dependence and withdrawal are referred to herein as cannabis use disorders. It is known to those of skill in the art that cannabinoids, including cannabidiol, are useful in treating cannabis use disorders.
Dystonia is a neurological movement disorder, with many known causes, and characterized by involuntary. continual muscular contractions causing twisting and repetitive movements or abnormal postures. Cannabinoids have been shown to reduce the muscular contractions characteristic of this disorder.
The etiological pathology of many diseases relates to the inflammatory processes that are regulated by an individual's immune system. Inflammation may result from (1) an otherwise appropriate immunoresponse to an outside trauma, such as brain swelling secondary to a closed head injury; (2) an overactive immunoresponse, such as an allergic reaction or dermatitis; or (3) an inappropriate auto-immunoresponse, such as certain forms of multiple sclerosis, inflammatory bowel disorders and arthritis. Regardless of the underlying cause of the inflammation, it is therapeutically desirable under these circumstances to regulate the immune system and lessen the inflammatory response. Cannabinoids have been shown to regulate various steps in the immune response and could show some therapeutic benefit in the treatment of certain inflammatory diseases such as psoriatic arthritis.
Rheumatoid arthritis affects approximately 0.5-1% of the United States population, and autoimmune diseases in general affect more than 20 million Americans. The pain associated with rheumatoid arthritis can often be disabling. Cannabinoids have been found to be useful as an adjunct treatment for rheumatoid arthritis and joint pain secondary to other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus.
In addition, transdermally administered cannabinoids have been found to be useful to alleviate pain and other conditions associated with deeper tissues, such as peripheral nerves, muscles and synovial tissues. Examples of conditions associated with deeper tissues responsive to cannabinoids include: peripheral neuropathic pain, including but not limited to, the peripheral neuropathic pain associated with diabetic neuropathy, ankylosing spondylitis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, osteoarthritis, rheumatoid osteoarthritis, synovitis and juvenile rheumatoid arthritis. When cannabinoids are administered transdermally to treat pain and other conditions associated with deeper tissues, including peripheral neuropathic pain, it may be useful to have significant local tissue and systemic levels of cannabinoids.
In addition to the above-discussed therapeutics benefits, cannabinoids, such as cannabidiol and cannabidiol prodrugs, present a variety of pharmacological benefits, including, but not limited to, anti-inflammatory, anti-convulsant, anti-psychotic, antioxidant, neuroprotective, anti-cancer, such as melanoma, and immunomodulatory effects.
Given these systemic therapeutic benefits, it would be advantageous to develop a composition in which a cannabinoid, such as cannabidiol or a prodrug of cannabidiol, is delivered systemically to achieve therapeutically effective plasma concentrations in a patient. However, cannabinoid oral dosage forms, including those comprising cannabidiol, must overcome several obstacles in order to achieve a therapeutically-effective systemic concentration. First, cannabinoids are generally highly lipophilic. Their limited water solubility thereby restricts the amount of cannabinoid available for absorption in the gastrointestinal tract. Second, cannabidiol, as with the other cannabinoids, undergoes substantial first-pass metabolism when absorbed from the human gastrointestinal tract. Finally, the oral bioavailability of any product is further diminished when a patient suffers from nausea or emesis, as either the patient avoids taking his oral medications or the oral dosage form does not remain in the gastrointestinal tract for a sufficient period of time to release the entire dose and achieve a therapeutic concentration.
Therefore, in view of the foregoing, it would be desirable to systemically deliver therapeutically effective amounts of a cannabinoid, such as cannabidiol or cannabidiol prodrug, to a mammal in need thereof for the treatment of one or more medical conditions responsive to cannabinoids, including pancreatic cancer, pancreatitis, pain, nausea or appetite stimulation, by a route of administration that does not depend upon absorption from the gastrointestinal tract of the mammal. One non-oral route of administration for the systemic delivery of cannabidiol is transdermal administration.
In addition, the epidermis and dennis of many mammals, such as humans and guinea pigs, contains enzymes which are capable of metabolizing active pharmaceutical agents which pass through the stratum corneum. The metabolic process occurring in the skin of mammals, such as humans, can be utilized to deliver pharmaceutically effective quantities of a cannabinoid, such as cannabidiol, to the systemic circulation of a mammal in need thereof. Described herein are prodrugs of cannabinoids, such as cannabidiol prodrugs, and compositions comprising prodrugs of cannabinoids that can be transdermally administered to a mammal, such as a human, so that the metabolic product resulting from metabolism in the skin is the cannabinoid which is systemically available for the treatment of a medical condition responsive to cannabinoid, for example pancreatic diseases, such as pancreatitis and pancreatic cancer.
Unfortunately, due to its highly lipophilic nature, cannabidiol is poorly absorbed through membranes such as the skin of mammals, including humans. Therefore, the success of transdermally administering therapeutically effective quantities of cannabidiol to a mammal in need thereof within a reasonable time frame and over a suitable surface area has been substantially limited.
Microneedles and COX Inhibitors
Enhancing the transdermal delivery of an active pharmaceutical agent by use of microneedle treatment has become an important area of research in the field of transdermal drug delivery. In addition, shorter microneedles may alternatively be used to topically administer an active pharmaceutical agent for local delivery to treat dermal conditions. It has further been found that a pharmaceutical composition comprising a cannabinoid or cannabinoid prodrug and a penetration enhancer can be administered to a mammal in conjunction with a microneedle array to treat a medical condition responsive to cannabinoids, including alcohol use disorders and pancreatic diseases, such as pancreatic cancer and pancreatitis. To enhance the transdermal or topical delivery of cannabinoids when administered in conjunction with microneedles, cannabinoid prodnigs (e.g., cannabidiol prodrugs) have been designed which typically have a greater water solubility than the parent cannabinoid molecule in order to take advantage of the aqueous pores created by microneedle use.
Microneedles are generally considered to be structures that are between about 20 μm and about 1000 μm in length capable of puncturing the outermost layer of the epidermis (stratum corneum) to create large-scale openings (relative to the size of the active pharmaceutical agent to be delivered there through) or pores through which one or more active pharmaceutical ingredients can be delivered. The depth of microneedle penetration is sufficient to enhance transdermal drug delivery but not sufficient to stimulate nerve endings. Therefore, the use of microneedles is pain-free. This aspect, as well as their economical and easy use, makes a system incorporating microneedle technology an attractive alternative for transdermal drug delivery.
The active pharmaceutical agents to be delivered in conjunction with microneedle technology range from large oligonucleotides to insulin, and highly water-soluble compounds. Compared to other methods of physically altering the cutaneous structure to aid in improving transdermal transport, microneedle delivery is a relatively simple technique. Microneedles are typically micromachined to increase permeability and decrease skin sensation and come in various forms, such as biodegradable polymers, silicon and stainless steel. Various researchers have studied the effects of microneedle-treated skin on increased permeation of mostly water soluble compounds through microneedle-created aqueous pores. It has been shown that the use of microneedles can enhance the permeation of many compounds including non-viral gene therapy vectors, desmopressin, insulin and naltrexone. Further, the application of microneedles has been shown to be pain free in comparison to a 26-gauge hypodermic needle.
The effectiveness of microneedles is dependent on the duration of time that the microneedle-created pores in the stratum corneum remain sufficiently open and “un-healed.” It is during this time that the enhanced delivery of the active pharmaceutical agent can continue. Recently there have been many determinations in pore lifetime and viability via a number of experiments involving transepidermal water loss, microscopic visualization and pharmacokinetic analysis. Transepidermal water loss (“TEWL”) measures the rate at which water escapes from the skin. TEWL values are commonly measured in damaged skin to determine water loss over time as a function of skin repair. By using an evaporimeter, an instrument that measures water loss, damage or changes in skin morphology can be determined by an increase in rate of water loss compared to “normal” skin. It has now been shown that TEWL readings are a valid measurement to observe the status of the permeability barrier.
Occlusive coverings, such as patches or hydrogels (which can be optionally incorporated into a patch), can be used to maintain microneedle-created pores. When a microneedle array was placed on the skin and removed without having been treated with an occlusive patch, the skin healed rapidly and TEWL readings returned to baseline levels within 30 minutes. In contrast, it has been demonstrated that under an occlusive environment, microneedle-created pores remained open for at least 48-72 hours. Likewise, microscopic visualization after staining has revealed that pores were present up to 72 hours. In hairless guinea pigs treated with 6-β-naltrexol hydrochloride, significant enhancement in microneedle pore viability was observed for 48 hours after microneedle exposure and occlusion, compared to untreated skin. It has also been shown that therapeutic levels of naltrexone (2.5±1.1 ng/mL) were achieved when a 16% naltrexone hydrochloride gel was administered to 6 healthy human volunteers after microneedle pretreatment. Further, it has been observed that when used in conjunction with microneedles, steady state naltrexone concentrations were achieved within two hours and remained for 48 hours. These results indicate that microneedle application to skin provides an alternative delivery route to oral, injectables and traditional passive transdermal delivery.
Even with the use of occlusive techniques (e.g., a patch which may optionally have a hydrogel incorporated therein) in conjunction with the microneedle-generated pores, it is, nevertheless, desirable to further extend the lifetime of microneedle-created pores. Such an increase in the duration of the pore opening can correspond to an increase in the interval between which doses are administered. Said differently, by increasing the duration of the pore opening, it is possible to reduce the frequency with which an active must be administered. Reductions in the dosage frequency have a positive impact on patient acceptance and compliance. Thus, it would be desirable to further enhance the viability of the microneedle-created pores in order to increase the rate, duration and extent of transdermal delivery of an active pharmaceutical agent.
It has been found that the rate and extent of cannabinoid transdermal absorption can be improved by administering a cannabinoid (e.g. cannabidiol) or a cannabinoid prodrug (e.g., a prodrug of cannabidiol) and optionally a penetration enhancer or co-solvent and/or a COX inhibitor, in pharmaceutical compositions in conjunction with microneedle arrays. It has further been discovered that by optimizing the composition excipients, the cannabinoid or cannabinoid prodrug can be administered, in conjunction with a microneedle array, on a schedule that encourages patient compliance, by reducing frequency of dosing to once or twice daily or even once or twice weekly.
Accordingly, a significant advancement in the art would occur with the development of a transdermal drug delivery system comprising pharmaceutical compositions, comprising a cannabinoid (e.g. cannabidiol) or a cannabinoid prodrug (e.g., a prodrug of cannabidiol), and a microneedle array in treatment of conditions responsive to cannabinoids. A further advancement would be the development of a transdermal drug delivery system comprising a pharmaceutical composition, comprising a cannabinoid (e.g. cannabidiol) or a cannabinoid prodrug (e.g., a prodrug of cannabidiol) and a microneedle array in treatment of (i) acute pancreatitis; (ii) chronic pancreatitis; (iii) pancreatic cancer; (iv) pain; (v) inflammation or (vi) alcohol use disorders.
Topical Delivery
In addition to the benefits of systemically administered cannabinoid discussed above, cannabinoids, including cannabidiol and prodrugs of cannabidiol, have been found to have localized benefits from topical administration. For example, topically administered cannabinoids have been found to be useful to alleviate pain and other conditions originating at or near the surface of the skin, including but not limited to, pain associated with post-herpetic neuralgia, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dereczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis, melanoma and psoriatic arthritis. Also, it has been found that the topical administration of cannabinoids, including cannabidiol, can inhibit the growth of hair.
In order to achieve these local benefits, it may be advantageous for the cannabinoid, (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol prodrug) to penetrate the stratum corneum but not be absorbed systemically. In such a case, the cannabinoid (e.g., cannabidiol) or cannabinoid prodrug (e.g., a prodrug of cannabidiol) would concentrate in the skin and/or pilosebaceous unit, thus maximizing its local effect. Not only does the localized effect increase the potential therapeutic benefit, it lessens the frequency and severity of side-effects associated with systemic cannabinoid administration because the amount of active compound circulating in the patient is reduced. The cannabinoid (e.g., cannabidiol) or cannabinoid prodrug (e.g., a cannabidiol prodrug) can be incorporated into a composition with an additional active moiety that is capable of improving the appearance and/or hydration of the skin.
Accordingly, a significant advancement in the art would occur with the development of a topical drug delivery system comprising a pharmaceutical composition, comprising a cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol prodrug) and a microneedle array in the treatment of condition responsive to cannabinoid therapy.